Overview

►Discovery of potent, selective, cell-active chemical probes for epigenetic targets using innovative methods.  Identification of new templates for optimization by the use of fragment screening and focussed library design.

The goal of the Epigenetic Chemical Probes group is to identify small molecules which interact with epigenetic targets with the following properties:-

  • IC50 (inhibitors) or Kd (antagonists) < 100nM.
  • >30-fold selectivity over targets in different branches of the phylogenetic tree, and other target families.
  • significant activity in cells < 1 mM.
  • the co-crystal structure of the ligand and protein is solved to better than 2.8A resolution.
  • the chemical probe is widely available to the scientific community without restrictions on use.

Group Members

Hong Wu

Hong received her Ph.D. in biochemistry from Dalhousie University and had her postdoctoral training at University of Torontowith Dr. Lori Frappier.  Hong then joined a Toronto-based biotech company as a scientist in the department of protein/antibody engineering, focused on generating recombinant antibodies for various biomarkers.    In 2004, Hong joined the SGC.  As the team-leader, Hong and her team have focused on solving crystal structures of human histone modification enzymes. Hong’s research interests include using structural and biochemical methods to study the molecular mechanism of epigenetic regulation of gene expression.

Hong Zeng

Hong Zeng received her Master’s degree from York University and has worked in various academic as well as industrial laboratories.  Her work experience ranges from molecular biology to cell biology, immunology and protein biochemistry.  She joined the SGC in 2004.

Santha Santhakumar
Suzanne Ackloo

Group Publications

2011

Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines.
Liu F, Barsyte-Lovejoy D, Allali-Hassani A, He Y, Herold JM, Chen X, Yates CM, Frye SV, Brown PJ, Huang J, Vedadi M, Arrowsmith CH, Jin J
J. Med. Chem.. 8.9.2011 54(17):6139-50. doi: 10.1021/jm200903z
PMID: 21780790

A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J
Nat. Chem. Biol.. 10.7.2011 7(8):566-74. doi: 10.1038/nchembio.599
PMID: 21743462

Small-molecule ligands of methyl-lysine binding proteins.
Herold JM, Wigle TJ, Norris JL, Lam R, Korboukh VK, Gao C, Ingerman LA, Kireev DB, Senisterra G, Vedadi M, Tripathy A, Brown PJ, Arrowsmith CH, Jin J, Janzen WP, Frye SV
J. Med. Chem.. 14.4.2011 54(7):2504-11. doi: 10.1021/jm200045v
PMID: 21417280

2010

Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
Liu F, Chen X, Allali-Hassani A, Quinn AM, Wigle TJ, Wasney GA, Dong A, Senisterra G, Chau I, Siarheyeva A, Norris JL, Kireev DB, Jadhav A, Herold JM, Janzen WP, Arrowsmith CH, Frye SV, Brown PJ, Simeonov A, Vedadi M, Jin J
J. Med. Chem.. 12.8.2010 53(15):5844-57. doi: 10.1021/jm100478y
PMID: 20614940

Accessing protein methyltransferase and demethylase enzymology using microfluidic capillary electrophoresis.
Wigle TJ, Provencher LM, Norris JL, Jin J, Brown PJ, Frye SV, Janzen WP
Chem. Biol.. 30.7.2010 17(7):695-704. doi: 10.1016/j.chembiol.2010.04.014
PMID: 20659682

2009

Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.
Liu F, Chen X, Allali-Hassani A, Quinn AM, Wasney GA, Dong A, Barsyte D, Kozieradzki I, Senisterra G, Chau I, Siarheyeva A, Kireev DB, Jadhav A, Herold JM, Frye SV, Arrowsmith CH, Brown PJ, Simeonov A, Vedadi M, Jin J
J. Med. Chem.. 24.12.2009 52(24):7950-3. doi: 10.1021/jm901543m
PMID: 19891491

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